The discovery of
leptin has significantly advanced our understanding of the metabolic importance of adipose tissue and has revealed that both
leptin deficiency and
leptin excess are associated with severe metabolic, endocrine, and immunological consequences. We and others have shown that a prominent role of
leptin in humans is to mediate the neuroendocrine adaptation to energy deprivation. Humans with genetic mutations in the
leptin and
leptin receptor genes have deregulated food intake and energy expenditure leading to a morbidly obese phenotype and a disrupted regulation in neuroendocrine and immune function and in
glucose and fat metabolism. Observational and interventional studies in humans with (complete) congenital
leptin deficiency caused by mutations in the
leptin gene or with relative
leptin deficiency as seen in states of negative energy balance such as lipoatrophy,
anorexia nervosa, or exercise-induced hypothalamic and neuroendocrine dysfunction have contributed to the elucidation of the pathophysiological role of
leptin in these conditions and of the clinical significance of
leptin administration in these subjects. More specifically, interventional studies have demonstrated that several neuroendocrine, metabolic, or immune disturbances in these states could be restored by
leptin administration.
Leptin replacement
therapy is currently available through a compassionate use program for congenital complete
leptin deficiency and under an expanded access program to subjects with
leptin deficiency associated with congenital or acquired lipoatrophy. In addition,
leptin remains a potentially forthcoming treatment for several other states of energy deprivation including
anorexia nervosa or milder forms of hypothalamic
amenorrhea pending appropriate clinical trials.